Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia

JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

Leukemia volume 33, pages 1400–1410 (2019)Cite this article

Subjects

Abstract

Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11:407–20.

    PubMed  CAS  Google Scholar 

  3. Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.

    PubMed  CAS  Google Scholar 

  4. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Google Scholar 

  5. Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell. 1999;3:159–67.

    Google Scholar 

  6. Dupuy F, Tabaries S, Andrzejewski S, Dong Z, Blagih J, Annis MG, et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 2015;22:577–89.

    PubMed  CAS  Google Scholar 

  7. Yu L, Lu M, Jia D, Ma J, Ben-Jacob E, Levine H, et al. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res. 2017;77:1564–74.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Chen Y, Ma X, Zhang M, Wang X, Wang C, Wang H, et al. Gadd45a regulates hematopoietic stem cell stress responses in mice. Blood. 2014;123:851–62.

    PubMed  CAS  Google Scholar 

  10. Lynch JR, Yi H, Casolari DA, Voli F, Gonzales-Aloy E, Fung TK, et al. Gaq signaling is required for the maintenance of MLL-AF9 induced AML. Leukemia. 2016;30:1745–8.

    PubMed  CAS  Google Scholar 

  11. Zhu N, Chen M, Eng R, DeJong J, Sinha AU, Rahnamay NF, et al. MLL-AF9-and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Investig. 2016;126:997–1011.

    PubMed  Google Scholar 

  12. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.

    PubMed  CAS  Google Scholar 

  13. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650–3.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Thorsteinsdottir U, Mamo A, Kroon E, Jerome L, Bijl J, Lawrence HJ, et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood. 2002;99:121–9.

    PubMed  CAS  Google Scholar 

  15. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–7.

    PubMed  CAS  Google Scholar 

  16. Andreeff M, Ruvolo V, Gadgil S, Zeng C, Coombes K, Chen W, et al. HOX expression patterns identify a common signature for favorable AML. Leukemia. 2008;22:2041–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Sroczynska P, Cruickshank VA, Bukowski JP, Miyagi S, Bagger FO, Walfridsson J, et al. shRNA screening identifies JMJD1C as being required for leukemia maintenance. Blood. 2014;123:1870–82.

    PubMed  CAS  Google Scholar 

  18. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006;125:483–95.

    PubMed  CAS  Google Scholar 

  19. Cho RJ, Campbell MJ. Transcription, genomes, function. Trends Genet. 2000;16:409–15.

    PubMed  CAS  Google Scholar 

  20. Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res. 2004;32(Database issue)):D277–80.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–40.

    PubMed  CAS  Google Scholar 

  22. Scheller K, Seibel P, Sekeris CE. Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol. 2003;222:1–61.

    PubMed  Google Scholar 

  23. Liu YY, Brent GA. Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation. Trends Endocrinol Metab. 2010;21:166–73.

    PubMed  CAS  Google Scholar 

  24. Aranda A, Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev. 2001;81:1269–304.

    PubMed  CAS  Google Scholar 

  25. Lee JW, Choi HS, Gyuris J, Brent R, Moore DD. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol. 1995;9:243–54.

    PubMed  CAS  Google Scholar 

  26. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009;2:ra73.

    PubMed  PubMed Central  Google Scholar 

  27. Dietrich PA, Yang C, Leung HH, Lynch JR, Gonzales E, Liu B, et al. GPR84 sustains aberrant beta-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood. 2014;124:3284–94.

    PubMed  CAS  Google Scholar 

  28. Blanpain C. Tracing the cellular origin of cancer. Nat Cell Biol. 2013;15:126–34.

    PubMed  CAS  Google Scholar 

  29. Krivtsov AV, Figueroa ME, Sinha AU, Stubbs MC, Feng Z, Valk PJ, et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia. 2013;27:852–60.

    PubMed  CAS  Google Scholar 

  30. George J, Uyar A, Young K, Kuffler L, Waldron-Francis K, Marquez E, et al. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells. Nat Commun. 2016;7:12166.

    PubMed  PubMed Central  Google Scholar 

  31. Stavropoulou V, Kaspar S, Brault L, Sanders MA, Juge S, Morettini S, et al. MLL-AF9 expression in hematopoietic stem cells drives a highly invasive AML expressing EMT-related genes linked to poor outcome. Cancer Cell. 2016;30:43–58.

    PubMed  CAS  Google Scholar 

  32. Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10:257–68.

    PubMed  CAS  Google Scholar 

  33. Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene. 2011;30:4297–306.

    PubMed  CAS  Google Scholar 

  34. Chao TK, Huang TS, Liao YP, Huang RL, Su PH, Shen HY, et al. Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer. PLoS ONE 2017;12:e0182166.

    PubMed  PubMed Central  Google Scholar 

  35. Wang YH, Israelsen WJ, Lee D, Yu VW, Jeanson NT, Clish CB, et al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell . 2014;158:1309–23.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Banerji V, Frumm SM, Ross KN, Li LS, Schinzel AC, Hahn CK, et al. The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia. J Clin Invest. 2012;122:935–47.

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Vick B, Rothenberg M, Sandhofer N, Carlet M, Finkenzeller C, Krupka C, et al. An advanced preclinical mouse model for acute myeloid leukemia using patients’ cells of various genetic subgroups and in vivo bioluminescence imaging. PLoS ONE 2015;10:e0120925.

    PubMed  PubMed Central  Google Scholar 

  38. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Chen M, Zhu N, Liu X, Laurent B, Tang Z, Eng R, et al. JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. Genes Dev. 2015;29:2123–39.

    PubMed  PubMed Central  CAS  Google Scholar 

  40. Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72:304–14.

    PubMed  CAS  Google Scholar 

  41. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18:3163–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30:488–96.

    PubMed  CAS  Google Scholar 

  43. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Bing Liu, Jin Yi Lim, Emma Ramsay, and the staff of the Mark Wainwright Analytical Centre for their assistance, and the CCI tumor bank for human AML samples. This work was supported by NHMRC APP1128824 and Cancer Council NSW RG15-11 (J.Y.W.).

Author contributions

J.R.L., B.S., P.C. and H.H.L.L. performed experiments; A.P. and P.H. partially contributed to bioenergetic analysis; B.V., I.J., K.S., T.T., T.L., M.H., M.D.N., A.J.W. and J.W. contributed to experimental reagents; J.Y.W. wrote the paper, managed the project, and supported the work.

Author information

Author notes

  1. These authors contributed equally: Jennifer R. Lynch, Basit Salik

Authors and Affiliations

  1. Cancer and Stem Cell Biology Group, Children’s Cancer Institute, University of New South Wales, Sydney, NSW 2052, Australia

    Jennifer R. Lynch, Basit Salik, Patrick Connerty, Halina Leung & Jenny Y. Wang

  2. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Binje Vick & Karsten Spiekermann

  3. German Cancer Consortium (DKTK), partner site Munich, Heidelberg, Germany

    Binje Vick, Irmela Jeremias & Karsten Spiekermann

  4. Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

    Binje Vick & Irmela Jeremias

  5. The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia

    Aster Pijning & Philip Hogg

  6. Department of Pediatrics, Dr. von Hauner Childrens Hospital, Ludwig Maximilians University, Munich, Germany

    Irmela Jeremias

  7. Experimental Leukemia and Lymphoma Research Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

    Karsten Spiekermann

  8. Children’s Cancer Institute, University of New South Wales, Sydney, NSW 2052, Australia

    Toby Trahair, Tao Liu, Michelle Haber & Murray D. Norris

  9. Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia

    Tao Liu, Murray D. Norris & Jenny Y. Wang

  10. Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia

    Andrew J. Woo

  11. Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

    Jianlong Wang

Authors
  1. Jennifer R. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basit Salik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Connerty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Binje Vick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Halina Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aster Pijning
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irmela Jeremias
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karsten Spiekermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Toby Trahair
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michelle Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Murray D. Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrew J. Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Philip Hogg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jianlong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jenny Y. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jenny Y. Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lynch, J.R., Salik, B., Connerty, P. et al. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia 33, 1400–1410 (2019). https://doi.org/10.1038/s41375-018-0354-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0354-z

This article is cited by

Search

Advanced search

Quick links